NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the Interaction of MDA5 and MAVS

Wu, X.M., Zhang, J., Li, P.W., Hu, Y.W., Cao, L., Ouyang, S., Bi, Y.H., Nie, P., Chang, M.X.
Journal of immunology (Baltimore, Md. : 1950)   204(8): 2216-2231 (Journal)
Registered Authors
Cao, Lu, Chang, Mingxian, Hu, Yiwei, Nie, Pin, Wu, Xiaoman
MeSH Terms
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Binding Sites
  • Cells, Cultured
  • DEAD-box RNA Helicases/metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Nod1 Signaling Adaptor Protein/deficiency
  • Nod1 Signaling Adaptor Protein/metabolism*
  • RNA, Viral/metabolism*
  • Signal Transduction/immunology*
  • Zebrafish
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/metabolism*
32169843 Full text @ J. Immunol.
Nucleotide oligomerization domain-like receptors (NLRs) and RIG-I-like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus-infected NOD1-/- zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5-MAVS and TRAF3-MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(I:C) and the formation of the MDA5a-MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1-MDA5 and NOD1-TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(I:C) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form-mediated immune signaling in vertebrates.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes